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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
  • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to a sulfonamide-containing indole compound and to an antiangiogenic effect thereof. More particularly, it relates to an antitumor agent, a cancer metastasis suppressor, a therapeutic agent for diabetic retinopathy, a therapeutic agent for rheumatic arthritis and a therapeutic agent for hematoma on the basis of an antiangiogenic effect.
• angiogenesis is a tumor-specific phenomenon and, in mature individuals, it is limited to the formation of endometrium, etc. accompanied by a menstrual cycle. Accordingly, its adverse effect is thought to be little as compared with known anticancer drugs.
• An antiangiogenic agent does not directly kill the cancer cells but cuts off the nutrient sources so that the said balance is inclined to apoptosis inducing dormant tumor or reduction in cancer whereby it is a drug which can be expected to exhibit an excellent effect (prolongation of life, inhibition of recurrence and suppression of metastasis) by a long-term therapy.
• angiogenesis participates in retinopathy or retinitis.
• eyesight gets worse and, when progressed, blindness is resulted.
• effective therapeutic drug therefor at present and effective therapeutic drugs have been demanded.
• WO 9301182 discloses antitumor agents due to a specific tyrosine kinase inhibiting activity of the compounds having an indole skeleton but they are indolylmethylene-2-indolinone compounds and are different from the present invention.
• WO 964016 discloses an antitumor agent due to a specific tyrosine kinase inhibiting activity of the compounds having an indole skeleton but they are 2-indolinone-3-methylene compounds and are different from the present invention.
• Sulfonamide compounds having an indole structure are disclosed in JP-A 7-165708 and JP-A 8-231505.
• An object of the present invention is to create a novel antiangiogenic agent and to provide an antitumor agent which shows a high safety and a sure effect as compared with conventional antitumor agents and is able to be administered for a long period.
• the present inventors have carried out an intensive study, found that the sulfonamide-containing indole compound represented by the following formula achieves the aimed object and accomplished the present invention. That is, the present invention relates to a sulfonamide-containing indole compound represented by the following formula (I), its pharmacologically acceptable salt or hydrates thereof.
• R 1 represents hydrogen atom, a halogen atom or cyano group
• R 2 and R 3 are the same as or different from and each represents hydrogen atom, a C 1 -C 4 lower alkyl group or a halogen atom
• R 4 represents hydrogen atom or a C 1 -C 4 lower alkyl group
• the ring A represents cyanophenyl group, aminosulfonylphenyl group, aminopyridyl group, aminopyrimidyl group, halopyridyl group or cyanothiophenyl group, provided that the case where all of R 1 , R 2 and R 3 are hydrogen atoms, where both R 2 and R 3 are hydrogen atoms, or where the ring A is aminosulfonyl group and both R 1 and R 2 are halogen atoms is excluded.
• R 1 is cyano group or a halogen atom
• at least one of R 2 and R 3 should not be a hydrogen atom.
• the present invention relates to a method for the prevention or therapy of the disease against which inhibitory of angiogenesis at the site of tumor, rheumatic arthritis or diabetic retinopathy is effective for the prevention or therapy, by administering a pharmacologically effective dose of the above-mentioned indole compound, its pharmacologically acceptable salt or hydrates thereof to a patient.
• the present invention further relates to a use of the above-mentioned indole compound, its pharmacologically acceptable salt or hydrates thereof for the manufacture of a preventive or therapeutic agent for the disease against which an antiangiogenic agent is effective for the prevention or therapy.
• the present invention furthermore relates to an antiangiogenic agent, an antitumor agent, a therapeutic agent for pancreatic cancer, a therapeutic agent for cancer of the colon, a therapeutic agent for gastric cancer, a therapeutic agent for breast cancer, a therapeutic agent for prostatic cancer, a therapeutic agent for lung cancer, a therapeutic agent for ovarian cancer, a cancer metastasis suppressor, a therapeutic agent for diabetic retinopathy, a therapeutic agent for rheumatic arthritis or a therapeutic agent for hematoma, which comprises the above-mentioned indole compound, its pharmacologically acceptable salt or hydrates thereof as an effective ingredient. It relates to a method for prevention, therapy and improvement by use of any of those pharmaceutical agents. Further, it relates to a use of the above compound for the manufacture of any of those pharmaceutical agents.
• a halogen atom means fluorine atom, chlorine atom, bromine atom or iodine atom.
• a C 1 ⁇ C 4 lower alkyl group means a linear or branched alkyl group such as methyl group, ethyl group, n-propyl group, n-butyl group, iso-propyl group, iso-butyl group and tert-butyl group.
• the indole compound represented by the above formula (I) may form a salt with an acid or with a base.
• the present invention also includes a salt of the indole compound (I) as well.
• the salt with an acid are an inorganic acid salt such as hydrochloride, hydrobromide or sulfate and that with an organic acid such as acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid or p-toluenesulfonic acid.
• Examples of the salt with a base are an inorganic salt such as sodium salt, potassium salt or calcium salt and that with an organic base such as triethylamine, arginine or lysine.
• the compound of the present invention (I) can be manufactured by various methods and representative ones among them will be as follows.
• Examples of the reactive derivative of the sulfonic acid (II) are commonly and well utilized reactive derivatives such as sulfonyl halide, sulfonyl acid anhydride and N-sulfonylimidazolide and the particularly advantageous example is a sulfonyl halide.
• the solvent used for the reaction those which dissolve the material substances and do not readily react with them are preferred.
• pyridine, tetrahydrofuran, dioxane, benzene, ethyl ether, dichloromethane, dimethylformamide and a mixed solvent consisting of two or more which are selected from them can be used.
• a basic solvent such as pyridine
• a basic substance such as an alkali carbonate or an organic tertiary amine may be added.
• the solvent which can be used is not limited to those listed here.
• the present reaction proceeds at room temperature but, if necessary, it may be cooled or heated.
• the reaction time is usually from 10 minutes to 20 hours and is optionally selected depending upon the type of the material compounds and the reaction temperature.
• an amino group is protected in the resulting product, a conventional deprotecting method such as treatment with an acid, treatment with an alkali and catalystic reduction may be carried out upon necessity whereby it is possible to give an indole compound (I) having a free amino group.
• the starting compound (II) and reactive derivative thereof include both known compounds and novel compounds.
• novel compounds they can be manufactured by applying the already-reported synthetic method for known compounds or by combining them.
• novel sulfonyl chloride may be manufactured by a method applying the synthetic methods mentioned in Chem. Ber., 90 , 841 (1957); J. Med. Chem., 6 , 307 (1963); J. Chem. Soc. (c), 1968 , 1265; Chem. Lett., 1992 , 1483; J. Am. Chem. Soc., 59 , 1837 (1937); J. Med. Chem., 23 , 1376 (1980); J. Am. Chem. Soc., 70 , 375 (1948); J. Am. Chem. Soc., 78 , 2171 (1956) etc.
• R 1a and R 3a are hydrogen atoms and R 2a is a halogen atom in the starting compound (III), it can be manufactured by a known synthetic method.
• R 2a and R 3a are the same as or different from and each represents hydrogen atom, a C 1 ⁇ C 4 lower alkyl group or a halogen atom (the case where both are hydrogen atoms is excluded) and R 1a is cyano group, it can be manufactured as follows.
• R 1a , R 2a and R 3a have the same meanings as defined above.
• R 1a , R 2a and R 3a have the same meanings as defined before; and DPPA means diphenyl phosphoryl azide.
• R 1a is a halogen atom
• it can be manufactured in such a manner that the formula (a) or the formula (g) in the above-mentioned reaction formulae (1) and (2) is halogenated by a conventional means and the nitro group is reduced or a protecting group of an amino group is eliminated.
• the compound of the present invention When the compound of the present invention is used as a medicament, it is administered either orally or parenterally.
• the dose varies depending upon degree of the symptom, age, sex, body weight and sensitivity difference of the patient, method of the administration, period for the administration, interval of the administration, property of the pharmaceutical preparation, type of the preparation, type of the effective ingredients etc., and is not particularly limited.
• intravenous administration it is 1-2000 mg, preferably 1-1500 mg and, more preferably, 5-1000 mg while, in the case of oral administration, it is usually 10-6000 mg, preferably about 50-4000 mg and, more preferably, 100-3000 mg per day for adults, and that is usually administered once daily or by dividing into up to three times a day.
• filler and, if necessary, binder, disintegrating agent, lubricant, coloring agent, corrigent, etc. are added to the main ingredient, followed by subjecting to a common method to make into tablets, coated tablets, granules, fine granules, powders, capsules etc.
• Examples of the filler are lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose and silicon dioxide;
• examples of the binder are polyvinyl alcohol, ethyl cellulose, methyl cellulose, gum arabic, hydroxypropyl cellulose and hydroxypropyl methyl cellulose;
• examples of the lubricant are magnesium stearate, talc and silica;
• examples of the coloring agent are those which are allowed to add to the pharmaceuticals; and examples of the flavoring agents are cacao powder, menthol, aromatic, peppermint oil, borneol, and cinnamon powder. It is of course no problem that such tablets and granules are appropriately coated with a sugar coat, gelatin coat or others if necessary.
• a pH adjusting agent, a buffer, a suspending agent, a solubilizer, a stabilizer, an isotonizing agent, a preservative, etc. are added, if necessary, to the main ingredient followed by subjecting to a conventional method to make into injections for intravenous, subcutaneous or intramuscular administration. At that time, it maybe made into a freeze-dried product by a common method if necessary.
• suspending agent examples include methyl cellulose, polysorbate 80, hydroxyethyl cellulose, gum arabic, tragacanth powder, sodium carboxymethyl cellulose and polyoxyethylene sorbitan monolaurate.
• solubilizer examples include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, macrogol and castor oil fatty acid ethyl ester.
• Examples of the stabilizer are sodium sulfite and sodium metasulfite.
• Examples of the preservative are methyl para-hydroxybenzoate, ethyl para-hydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol.
• the inhibition degree of angiogenesis which was observed when aorta pieces of rat were incubated in collagen was defined as an antiangiogenic effect. That is, the aorta excised from male rat of Sprague-Dawley strain (10-12 weeks age) was washed with a Hanks' solution so that fat tissues around there were removed minutely. The aorta was incised to prepare pieces of 2 mm square and they were allowed to stand in a 24-well plate holding the endothelial cells upside. Then, 500 ⁇ l of neutralized Type I collagen (Cell Matrix Type I-A; manufactured by Nitta Gelatin) were poured over each well and allowed to stand at room temperature for about 20 minutes in a clean bench to solidify the gel.
• Cell Matrix Type I-A manufactured by Nitta Gelatin
• MCDB 131 medium manufactured by Chlorella Kogyo
• 500 ⁇ l of MCDB 131 medium were added thereto followed by incubating in a CO 2 incubator (5% CO 2 ) at 37°C.
• the culture medium was exchanged with 500 ⁇ l of MCDB 131 medium containing the test compound and the incubation was continued.
• the medium was again exchanged with 500 ⁇ l of MCDB 131 medium containing the test compound and, at the stage of the 7th day from the initiation of addition of the test compound, numbers of capillaries formed around the aorta were counted under a microscope.
• the solution containing the test compound was prepared in a three-fold dilution system where 10 ⁇ g/ml was the highest concentration.
• phosphate buffer containing 0.33% of 3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) was added thereto and incubation was continued for 3-4 hours. Then, after the supernatant liquid of the culture was removed, 100 ⁇ l of dimethyl sulfoxide (DMSO) was added to dissolve a formazane which was formed in the cells and the absorbance at the wave length of 540 nm was measured by use of plate reader (manufactured by Corona Denki).
• DMSO dimethyl sulfoxide
• DMED Dulbecco-modified Eagle medium
• penicillin 100 ⁇ g/ml of streptomycin were adjusted to 2 ⁇ 10 4 cells/ml and each 100
• the dose of 50 mg/kg, 100 mg/kg or 200 mg/kg was continuously administered per os two times a day and the size of the tumor on the 22nd day from the beginning of the administration was compared with that in the group to which no drug was administered.
• the result was 37%, 30% and 11%, respectively in the KP-1 cell strain derived from human pancreatic cancer and 0.2%, 0.3% and 0.0%, respectively in the HCT 116 cell strain derived from human cancer of the colon in the case of a group to which the compound of Example 1 was administered for example.
• the compound of Example 1 showed a significant antitumor effect.
• the compound of the present invention can be expected to exhibit an excellent effect in view of efficacy and safety as compared with the known bactericidal antitumor agents which directly target cancer cells.
• the compounds of the present invention have an excellent antiangiogenic effect and are useful as antitumor agents for pancreatic cancer, cancer of the colon, gastric cancer, bread cancer, prostatic cancer, lung cancer and ovarian cancer and also as therapeutic agents for diabetic retinopathy, rheumatic arthritis and hematoma.
• the extract was washed with a saturated aqueous solution of sodium bicarbonate, water and brine successively, and dried over magnesium sulfate.
• the solvent was evaporated, a mixed solution of diethyl ether and hexane was added to the residue and the crystals were collected by filtration to give 16.0 g of the title compound.
• the resulting compound was dissolved in 160 ml of 1,3-dimethyl-2-imidazolidinone followed by adding 716 mg (3.24 mmol) of basic copper carbonate and stirring at 185°C for 2 hr.
• the reaction solution was poured into water, the resulting insoluble matters were filtered off, and the resulting filtrate was extracted with ethyl acetate.
• the organic layer was washed with water and brine successively, dried over magnesium sulfate and concentrated. Then, the resulting residue was purified by silica gel column chromatography to give 4.50 g of the title compound.
• the title compound was obtained by the same manner as in Production Example 23.
• the title compound was obtained by the same manner as in Production Example 24.
• the title compound was obtained by treating with N-chlorosuccinimide in a solution of the compound of Production Example 31 in tetrahydrofuran/dimethylformamide.
• the compound (700 mg, 4.09 mmol) of Production Example 12 was dissolved in 20 ml of tetrahydrofuran, and then 1.3 ml (16.1 mmol) of pyridine and 950 mg(4.48 mmol) of 6-chloro-3-pyridinesulfonylchloride were added thereto. After stirring at room temperature for 2 hours, a 1N hydrochloric acid was added thereto to adjust to pH 1-2 and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine successively, dried over magnesium sulfate and concentrated. Then, the resulting residue was purified by silica gel column chromatography to give 1.16 g of the title compound.

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